Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. SMA is an autosomal recessive neuromuscular disorder characterized by degeneration of the anterior horn motor neurons in the spinal cord, leading to symmetrical muscle weakness and atrophy. It is caused by mutations or deletions in the gene encoding the survival motor neuron protein (SMN), a ubiquitous protein involved in mRNA splicing. It is still unknown why motor neurons are so specifically vulnerable to low levels of SMN and how SMN deficiency selectively causes motor neuron cell death. Currently there is no cure or treatment available to stop its progression. We and others have shown that low levels of SMN lead to axonal growth defects, impaired 2-actin mRNA transport and reduced 2-actin protein levels in growth cones of motor neurons. These findings represent the first known molecular defect in SMN-deficient neurons and suggest an axon-specific function for SMN. We hypothesizes that SMN may act as an important cofactor for the assembly, transport and/or local translation of 2-actin mRNA granules in axonal growth cones. Defects in axonal mRNA localization and translation of 2-actin may contribute to the axonal dysfunction and neurodegeneration typical of SMA. Previous efforts to develop treatments for SMA did not directly target axonal defects in SMN-deficient motor neurons. In this translational research application for funding to the NIH, we propose to perform cell-based high throughput screens for drugs that correct functional deficits in SMN-deficient motor neurons. Firstly, we will use pluripotent stem cell-derived motor neurons to identify drugs that enhance transport of 2-actin mRNA into axonal growth cones. Secondly, we will screen for drugs that raise 2-actin protein levels in growth cones. Novel drug candidates identified in these screens will be validated for effectiveness through a progressive series of tests in cultured primary motor neurons and SMA mouse models. Given the human toll of this disease and the lack of an effective therapy, it is our goal to translate recent progress in understanding the function of SMN in motor neurons into the development of effective drugs for the treatment of SMA. PUBLIC HEALTH RELEVANCE: We propose to use stem cell-derived motor neurons to screen for drugs for the treatment of axonal defects in spinal muscular atrophy. Molecules that raise 2-actin mRNA and protein levels in axons and growth cones have the potential to be used as drugs for the treatment of spinal muscular atrophy and possibly other neurodegenerative human diseases where axonal transport and synaptic defects are implicated.